IS 12572 ( Pad 11 ) 1990 ( Reaffirmed 2006 ) Indian Standard GUIDE FOR EVALUATION OF MEDICAL DEVICES FOR BIOLOGICAL HAZARDS PART 11 METHOD OF TEST FOR EYE IRRITATION UDC 615'4 : 614'8 : 616-022 : 617-7-002 @ BIS 1990 BUREAU MANAK OF BHAVAN, INDIAN STANDARDS ZMAR MARG 9 BAHADUR SHAH NEW DELHI 110002 November 1990 Price Group 2 Medical Instruments and Disposables Sectional Committee, MHD 12 FOREWORD This Indian Standard ( Part 11 ) was adopted by the Bureau of Indian Standards on 20 March 1990, after the draft finalized by the Medical Instruments and Disposables Sectional Committee had been approved by the Medical Equipment and Hospital Planning Division Council. This part ( Part 11 ) is one of the series of methods of test for assessing the biological hazards of medical devices that directly come in contact with body tissues or substances that are to be introduced into the body by means other than oral. Part 2 of this standard provides guidance on selection of the recommended methods of test for the assessment of biological hazards in medical devices which has been referred to in this part. This standard is proposed to be published in 12 parts. Other parts are as follows: Part 1 Part 2 Part 3 Part 4 Part 5 Part 6 Part 7 Part Part Part Part 8 9 10 12 Terminology Selection of biological methods of test Method of testing by tissue implantation Method of test for systemic toxicity : Assessment of acute toxicity medical devices Method of test for intracutaneous reactivity of extracts from medical Method of test for systemic toxicity : Assessment of pyrogenicity in from medical devices Methods of test for sensitization : Assessment of potential of medical delayed contact dermatitis Method of test for skin irritation of extracts from medical devices Method of test for skin irritation by solid medical devices Methods of biological testing and evaluation of dental materials Method of test for toxicity to cells in culture of extracts from medical of extracts from devices rabbits of extracts devices to produce devices In the preparation of this standard, assistance has been derived from BS 5736 : Part 9 : 1986 `Evaluation of medical devices for biological hazards Part 9 Method of test for eye irritation' issued by the British Standards Institution, UK. IS 12572 ( Part 11 ) : 199aj fndian Standard GUIDE FOR EVALUATION OF MEDICAL DEVICES FOR BIOLOGICAL HAZARDS PART 11 METHOD OF TEST FOR EYE IRRITATION 1 SCOPE 1.1 The standard ( Part I1 ) describes a method of test designed to assess the ocular irritation of leachable endogenous or extraneous Substances present in or on a medical device. 1.2 This method specilies the use of either a polar solvent or a nonpolar solvent to obtain extracts. The polar solvent ii used to obtain extracts from devices that are intended for use with polar liquids and the non-polar solvent is used to obtatn extracts from dcvtces that are intended for use either with or in contact with non-polar liquids. In both the cases the extracts are administered IO the rabbit eye, using a multiple instillation procedure for the polar solvent extract and a single instillation procedure for the non-polar Solvent extract. 1.3 This method of test is recommended for the initial assessment of devices in categories B> and E2 of Part 2 of this standard, i*ltended for use with polar or non-polar solvents. Category B2 2.2 Medical Device An instrument, apparatus, implement, appliance, implant or other similar or related article, which, is intended for use in the treatment of humans, jn diagnosis or for contraceprion but excluding any' device that achieves its principal intended purpose:' through chemical action within or on the body. 2.3 Test Materials The final product is to be tested. 3 ANIMALS AND HUSBANDHY or sample of final product that_ 3.1 A minimum single Strain shnll of three albino rabbits of a: shall be used to test each extract. They be healthy adults of weighing between 2 kg and 3 kg. cages with perforated either sex. 3.2 The animals shall be housed individually bedding material. food and water. 3.3 The animals animal laboratory to testing. 4 PREPARATION PRODUCTS 4.1 Test Material ina or wire mesh floors without They shall have free access to. shall be acclimatized in thefor a minimum of 5 days prior OF EXTRACTS OF FINAL. Those intended for long term ( long term covers a period from a few months to permment use ) or repeated contact with cornea and conjunctive, for example contact lenses. Category E, Those intended to be used to contain or adminiskr substances by means of routes oth:r than those in category El for example ejxkop w;ltain:rs. 1.4 The assessment of the result should be carried out by a toxicologist who is aware of the conditions of use of the final product and has appropriate chemical and biological data concerning it ( see 3.3 and 3.4 of Part 2 of this standard ). 2 DEFINITIONS For the purpose dolinitiom shall 4.1.1 Test material from pre-sterilized devices, ( refers to devices obtained steriiized from the manufacturer or supplier ) shall be handled asceptically throughour the extraction and test procedure. 4.1.2 Test material from devices which arc normally supplied non-sterile but are Tao be sterilized before use shall be sterilized before the extraction procedure and handled aseptically throughout the extraction and test procedure. 4.1.3 Test material from devices not required to be sterile in use shall be use:i as supplied and handlcJ aseptically throughout the cxtruction and. test procedure. 1 of this standard apply. the following 2.1 Final Product A medical dcvicc ii1 it's ready-to use state. I@ 12572( Part ( .4.2 Extractants .4.2.1 11 ) : 1990 4.4 Method of Extraction Polar Solvent Sterile saline solution chloride. .4.2.2 Non-polar Solvent containing 9 g/l sodium Using either the polar or non-polar solvent as extractant, as appropriate, prepare in accordance with 4.1 and 4.3 sufficient volume of extract of the test material for administration as described in 5. 4.4.1 For example #or cottonseed sesame .oiI Ph. Eur. or USP or IP oil USP or IP. any the are are 4.4.2 The period of contact between extractant and test material shall be not less than 2 h and need not be more than 72 h. 4.4.3 Record for the test report, the precise conditions of extraction and, if applicable, of sterilization. 5 TEST PROCEDURE 5.1 Preparation of Animals No longer than 24 h before commencement of the test, examine both eyes of each rabbit with a slitlamp microscope for evidence of ocular abnor. mality. If either eye shows any abnormality, reject the animal and replace by another rabbit. NOTE - It is essential that the oil used or non- polar solvent used are non irritant to rabbit eye under the conditions of test and competible with the device under test, and represeu:a:ive of non-polar liquids to be used with or in contact with the device. 4.3 Principles of Extraction ,4.3.1 The test material shall be representative .of the final product, or that component of the final product chat is to be tested. ,4.3.1.1 To achieve this, the test material may .consist of small pieces of the final product, or of one or more intact devices. For multicomponent .&vices it may be appropriate to test separately the individual components of the device, ,4.3.1.2 The quantity of any endogenous or ,extraneous substances extracted is related to the surface area of the aample ( interfacial area ) with which the txtractant is brought into contact. .4.3.1.3 The concentration of any endogenous or extraneous substances in the extract, and hence the dose delivered to the test animal, depends on both interfacial area and final extract volume. 4.3.1.4 The interfacial area per unit volume of (extract has to be taken into consideration when .the dose given to the test animal is related to the likely exposure of the device to man. ,4.3.2 To render test as sensitive as possible, the ratio between interfacial area and final extract ,voIume shall be as high as is pracricable. The interfacial area per millilitre of final extract volume shall not be less than 12 5 cm". 4.3.3 The technique to be used in exposing the ,test material to the extractant shall be selected according to the requirements of 4.3.1 and 4.3.2. Fragmentation of the test material may be used to increase the interfacial area. 4.3.4 Extraction conditions shall simulate as closely as possible, the conditions under which the device will normally be used. 4.3.5 During the extraction, 27" i 3 `C shall be representative of room temperature and 37" f 2°C ,shall be representative of body temperature. 5.1.1 Sodium fluorescein 2% BP ( or IP ) may be used to help make visible any cornea1 damage. 5.2 Application of Extracts Using a sterile 1 ml glass syringe, instil O-1 ml of the extract into one eye of each of the three rabbits by gently pulling the lower lid away from the eyeball and dropping the extract into the conjuctival sac. Gently hold the eyelids together for approximately 4s, following instillation. 5.2.1 Do not treat the contralateral eye of each animal so that this serves as a control. 5.2.2 For the polar extract repeat this procedure once daily for five consecutive days. 5.3 Observation of Animals 5.3.1 Animals Receiving Polar Extract Examine both eyes of each animal immediately before and 1 h after each instillation. Carry out the examination using natural day5.3.1.1 light or a similar source of ilhImination. out the 5.3.1.2 After the fifth instillation carry examination using a slit-lamp microscope. 5.3.1.3 Grade to and record any reactions observed trle scale for grading ocular lesions given in Table I. according 2 IS 12572 ( Put Table 1 Scale for Grading Ocular Lesions ( Clause 5.3.1.3 ) Area (1) Cornea Reaction (2) Degree of Opacity 11) : 1990 5.3.2 Animals Receiving Non-polar Extract Numerical Grading (3) ( most dense area used 1 .O both eyes of each animal approximately 1 h, 24 h, 48 h and 72 h after instillation. Carry out the examination using natural daylight or a similar source of illumination. 5.3.2.2 After 72 h carry out using a slit-lamp microscope. 5.3.2.3 Grade 5.3.2.1 Examine a) No opacity b) Scattered or diffuse areas, details of iris clearly visible c) Easily discernible translucent areas, details of iris slightly obscured d) Opalescent areas, no details of iris visible, size of pupil barely discernible e) Opaque, iris invisible Area of cornea involved 1 2 3 the examination 4 1 and record any reactions observed according to the scale for grading ocular lesions given in Table 1. 5.3.2.4 When a) One-quarter or less but not zero b) Greater than one-quarter but not more than half c) Greater than half but not more than three-quqrrers d) Greater than three quarters, up to whole area WS 2 3 4 the eyes are examined using a slitlamp microscope, sodium fluorescein 2 percent BP ( or IP ) may be used to help make visible any cornea1 damage. Values a) Normal b) Folds above normal. congestion, swelling, circumcorneal injection ( any or all or combination of any of these ) iris still reacting to light ( sluggish reaction is positive ) c) No reaction to light, haemorrhage, gross destruction ( any or all of these ) Conjunctive RPdners ( Refers to palpehral bulhnr conjuncrivae excluding and iris ) and cornea 0 1 NOTE - A usseful guide to assessing ocular lesions is given in Illustrated guide for grading eye irritation caused by hazardous substances' published by US Consumer Product Safety Commission, Washington DC 20 207 USA. 2 6 PRESENTATION OF RESULTS a) Vessels normal b) Vessel< definitely injected above normal c) More diffuse, deeper crimson red, individual vessels not easily discernible d) Diffuse beefy red Chemosis 0 The results shall be submitted which includes. in a test report 1 2 3 0 1 2 3 4 a) a complete extractlon, record ot' the method of b) the procedures followed, cl the results of observation, and a) No swelling b) Any swelling above normal ( nictitating membrane ) c) Obvious swelling with pxtial of lids d) Swelling with lids about half e) Swelling with lids about half to completely closed Discharge includes eversion closed closed 4 any other relevant data necessary for the assessment of results as described in 7. 7 ASSESSMENT 0 1 OF RESULTS a) No discharge b) Any amount different from normal ( does not include small amount observed in inner canthus of normal animals ) c) Discharge with moistening of the lids and hairs adjacent of lids d) Discharge with moistening of the lids and hairs and coclsiderablr area around the eye 2 3 The overall assessment of the test results shall be carried out by a toxicologist, If the toxocologist considers the results to be either inconclusive or mvalid, the test shall be repeated using different rabbits, new extracts and if necessary, different extractants. 3 Standard Mark The use of the Standard Mark is governed by the provisions of the Bureau of Indian The Standard Mark on Standards Act, 1986 and the Rules and Regulations made thereunder. products covered by an Indian Standard conveys the assurance that they have been produced to comply with the requirements of that standard under ? well defined system of inspection, testing and quality control which is devised and supervIsed by BIS and operated by the producer. 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Revision of Indian SMr Indian Standards are reviewed periodically and revised, when necessary and amendments, if any, are issued from time to time. Users of Indian Standards should ascertain that they are in possession of the latest amendments or edition. Comments on this Indian Standard may be sent to BIS giving the following reference:. Dot : No. MHD 12 ( 2090 ) Publication Text A&ted Amta Issaed Sineo Amend No. Date of Issue BUREAU OF INDIAN STANDARDS Headquarters : Manak Bhavan, 9 Bahadur Shah Zafar Marg, New Delhi 1loo02 Telephones : 331 01 31, 331 13 75 Regional 05ces : Central I Manak Bhavan, 9 Bahadur Shah Zafar Marg NEW DELHI 110002 Eastern : l/14 C. I. T. Scheme VII M, V. I. P. Road, Maniktola CALCUTTA 700054 Northern : SC0 445-446, Sector 35-C, CHANDIGARH 160036 Southern : C. I. T. 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